Gemcitabine (2-deoxy-2′,2′-difluorocytidine)

is disclosed in U.S. Pat. No. 4,526,988, which discloses a synthetic method comprising the preparation of 2-deoxy-D-erythro-2,2-difluoro-ribofuranose protected at the hydroxyls at the 3- and 5-positions with a suitable protective group P

by reduction of 2-deoxy-D-erythro-2,2-difluoro-ribofuranos-1-ulose protected at the hydroxyls at the 3- and 5-positions

wherein P is as defined above
with a hydride, preferably with diisobutyl-aluminium hydride in toluene (DIBAL).
The reduction with lithium aluminium hydride was described in Chem. Abstr. XP 002542350. 2008:1103450.
U.S. Pat. No. 5,945,547 indicates benzoate as a particularly preferred protective group and it claims 2-deoxy-D-erythro-2,2-difluoro-ribofuranos-1-ulose-3,5-dibenzoate, while U.S. Pat. No. 4,965,374 claims a method for its recovery.
Protected 2-deoxy-D-erythro-2,2-difluoro-ribofuranose is subsequently transformed into Gemcitabine by transformation of the hydroxyl at the 1 position into a leaving group, preferably methanesulfonate, reaction with protected acetyl-cytosine to afford protected Gemcitabine and removal of the protective groups. Gemcitabine base can then be transformed into a pharmaceutically acceptable salt, such as the hydrochloride usually employed in therapy.
The synthesis of high purity Gemcitabine hydrochloride, according to the regulatory requirements contemplated by the Official Pharmacopoeias, requires purification of the beta anomer by separation of the alpha anomer, which is difficult and often involves costly chromatographies.
Moreover, the synthesis processes involving 2-deoxy-D-erythro-2,2-difluoro-ribofuranos-1-ulose-3,5-dibenzoate still suffer from some problems, such as the remarkable energy waste necessary to maintain the low temperatures (between −80 and −60° C.) required during the reduction reaction of the carbonyl group with DIBAL.
The known processes for the purification of Gemcitabine base from the hydrochloride involve the use of high volumes of solvent (70 to 100 volumes per gram of product) and are not ideal from the yield point of view. See in particular U.S. Pat. No. 4,965,374, WO 2006/095359, WO 2005/095430 and WO 2007/049294.